Klotho restoration by epigenetic intervention prevents renal fibrosis / 医学研究生学报

Renal fibrosis is a pathological process presented in all chronic kidney diseases and lacks effective treatment. Renal anti-aging protein Klotho displays impressive anti-renal fibrosis capacities, but sustainedly depressed during the initiation and progression of renal fibrosis due to aberrant epigenetic modifications, making Klotho a potential target of epigenetic intervention in anti-renal fibrosis therapy. The author has performed a series of studies and first established TGFb as an essential upstream pathological factor that causes Klotho suppression by inhibiting miR-152 and miR-30. This inhibition subsequently induces DNMT1 and DNMT3a and leads to Klothopromoter hypermethylation and Klotho suppression. Further, it has been found that Rhein from the Chinese medicinal herbal plant and a specific inhibitor of histone deacetylase (HDAC) 3 are capable of either inhibiting the aberrant DNMT1/3a induction and Klotho promoter DNA hypermethylation or enhancing PPARg acetylationat lysine 240/265 and its up-regulation of Klotho, resulting in Klotho restoration and reduced renal fibrosis and the associated renal and bone injuries. Therefore our findings have revealed the distinct epigenetic features of Klotho suppression in renal fibrosis and demonstrated the promising potentials of Klotho-targeted strategies in the treatment of renal fibrosis and the related disorders.

Effects of triptolide on the pharmacokinetics of cyclophosphamide in rats: a possible role of cytochrome P3A4 inhibition / 中国结合医学杂志

<p><b>OBJECTIVE</b>To evaluate the effect of a 10-day course of triptolide (TP) on rat cytochrome (CY) P3A4 activity, and on the pharmacokinetics of cyclophosphamide (CPA).</p><p><b>METHODS</b>In the pharmacokinetics experiment, rats were orally given 0.9% NaCl solution (n=5) and TP [1.2 (mg/kg·d)] for 10 days and a single dose of CPA was administered intravenously (100 mg/kg) to rats on day 11. Blood samples were collected up to 4 h at predetermined time intervals, the plasma concentration of CPA was determined by high performance liquid chromatography (HPLC) and pharmacokinetic parameters were determined. In the in vitro CYP3A4 activity inhibition research, rat blank liver microsomes were divided into 3 groups: a control group, a TS (5 μL, 200 μmol/L) with TP (5 μL, 12.5 μmol/L) group, a TS with ketoconazole (5 μL, 1 μmol/L) group. Concentration of 6β-hydroxylated testosterone (6β-OHT) in liver microsomes was measured by HPLC and the activity of CYP 3A4 was calculated through the following formula: Einhibitor/Econtrol × 100%=Cinhibitor/Ccontrol × 100%.</p><p><b>RESULTS</b>Compared with the control group, the area under the plasma concentration-time curve (AUC0-∞) of CPA was significantly increased by 229.05% pretreated with TP (P<0.01). Peak plasma concentrations (Cmax) of CPA was significantly increased and plasma half-life was correspondingly extended. The CYP3A4 activity was significantly inhibited by ketoconazole 93.5%±0.2% and TP 84.6%±0.3% compared with the control group (P<0.01 and P<0.05, respectively).</p><p><b>CONCLUSION</b>Our results strongly suggested that long-term oral intake of TP can distinctly inhibit the CYP3A4 activity and this inhibition evidently decrease the formation of toxic metabolites of CPA.</p>

Human buccal mucosa microbiota succession across age / 华西口腔医学杂志

<p><b>OBJECTIVE</b>This investigation aimed to examine how buccal mucosa microbiome succeeds in a healthy population with different ages and dentition stages.</p><p><b>METHODS</b>Twenty-five subjects were recruited and subdivided into five groups: primary dentition group, mixed dentition group, adolescent group, adult group, and elderly group. Individual mucosal microbiota was obtained by gently scraping both sides of the buccal mucosa with a cotton swab. Microbial diversity was analyzed by polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE).</p><p><b>RESULTS</b>1) The composition of buccal mucosa microbiota has great intra-individual divergence. 2) The average band numbers of the primary dentition group, mixed dentition group, adolescent group, adult group, and elderly group were 21.2 +/- 4.0, 17.8 +/- 3.9, 15.8 +/- 4.3, 16.8 +/- 3.7, and 22.2 +/- 6.5, respectively. No between-group differences was observed (P > 0.05), indicating that predominant strains in the oral cavity may be stable throughout an individual's lifetime. 3) The Shannon indices of primary dentition group, mixed dentition group, adolescent group, adult group, and elderly group were 1.73 +/- 10.2, 1.43 +/- 0.1, 1.05 +/- 0.2, 1.45 +/- 0.2, and 1.63 +/- 0.3, respectively. A significant between-group difference was observed (P = 0.003), indicating that the microbial diversity of the buccal mucosa decreases from childhood through adolescence, but increases from adult through senescence. 4) The clustering analysis showed that most of the samples in the same group clustered together, indicating higher intra-group community structure similarity.</p><p><b>CONCLUSION</b>Composition of the buccal mucosa microbiota was different among age groups. Adolescence may be an essential turning point of microbial ecology succession throughout life.</p>